In addition to developmental functions, estrogens have been found to reduce incidence of coronary heart disease (1), maintain bone mineral density (2), and in the CNS, promote neuronal survival (3, 4) and hippocampal neurogenesis (5-7). Neuro-imaging studies reveal that estrogen therapy improves cerebral blood flow and performance in hippocampal-dependent memory tasks in humans (8, 9). Other observational studies have found that estrogen helps alleviate age-related cognitive decline by preserving executive function in the frontal lobe (10).
Raloxifene (EVISTA) is a second generation selective estrogen receptor modulator (SERM) used clinically for the treatment of osteoporosis in postmenopausal women, which acts as an antiestrogen in breast and endometrium (17-21). Raloxifene, however, increases the lifetime risk of thromboembolism (23). Raloxifene has been found to enhance levels of vasodilatory NO through action on endothelial nitric oxide synthase (eNOS) (24-26), and, the increased thromboembolic events have been attributed to decreased eNOS activity in postmenopausal women (27). NO inhibits thrombus formation through inhibition of platelet recruitment, adhesion and aggregation (28). The next generation SERM, arzoxifene (41, 42), a prodrug of desmethylarzoxifene (DMA) was designed to improve the pharmacokinetic (PK) profile relative to raloxifene, from which it differs by only one atom (43, 44).